When an artificial joint has been implanted for treating articular rheumatism or arthrosis deformans and caused loosening between the artificial joint and bone tissues after long period service, it should be replaced by a new one through artificial joint revision surgery. On an artificial joint revision surgery, bone grafting with an autologous bone derived from the patient, or the like, is carried out in order to supplement a part of lost bone. Bone grafting has a feature that a bone protein contained in grafted bone promotes resorption of the grafted bone and conversion to an autologous tissue, therefore it has an advantage that reconstruction of a joint function becomes possible even though reconstruction with a prosthesis is impossible. Further, bone is a tissue superior in regenerative capacity, it may be regenerated into a nearly original form by proper reintegration and fixation in case of a fracture.
However, autologous bone grafting is a method which own bone is cut out from a certain part of a patient as a block, the obtained bone is transplanted to deficient part as a block, or after crushing to a granular or powder form. The method is an advantage of high safety because own bone is utilized although, pains are severe at the bone collecting part in the case of a large bone defect region, the recovery period after the bone grafting surgery becomes longer, and sometimes it is very difficult to find a donor supplying a bone for bone grafting. To avoid such drawbacks, allogeneic bone grafting using a donor-derived bone instead of an autologous bone is conducted, and further, various bone graft materials have been also developed.
For example, there is a composition used for promoting bone formation in arthrodesis which includes a platelet-derived growth factor solution, a biocompatible matrix containing polysaccharides, and a scaffold material such as calcium phosphate (Patent Literature 1). In the example thereof, 1.0 mg/mL of platelet-derived growth factor is dropped to calcium phosphate in the average diameter of 1000 to 2000 μm for preparing a composition, and the composition is coated on a bone to be fused in a joint. As the result, the composition exhibits bone bridging and joint adhesion equivalent to autologous bone grafting.
Further, there is a bone graft material on which surface a cell adhesion inducing peptide having an RGD amino acid sequence, or a tissue growth factor-derived peptide is fixed (Patent Literature 2). The bone graft material adhering on the surface a tissue growth factor capable of obtaining a tissue regeneration effect and a peptide having active site of an extracellular matrix protein exhibits allegedly a stable and sustainable pharmacological effect, even though the concentration of the peptides is low. In the example thereof surfaces of a bovine bone-derived bone mineral particle are treated with 3-aminopropyltriethoxysilane to form an amine residue, the particles are bound with a crosslinking agent of 1,4-bis-maleimidebutane added thereto, then reacted with a cell adhesion inducing peptide to fix the peptide, and prepare a bone graft material. The material exhibits allegedly superior regenerative power compared to a bone graft material without the fixed peptide.
There is also a bone graft fragment composition prepared by drying a fragment of a cell-free tissue substrate together with a fragment of a demineralize bone material (Patent Literature 3). A cell-free tissue substrate such as collagen obtained from an epithelial cell has capability for supporting cell recognition and cell association, as well as cell spreading, cell proliferation, and cell differentiation, a demineralize bone material has physiological characteristics of natural bone important for a success of bone grafting. When the obtained bone graft fragment composition is coated on a transplantation or implantation part after hydration, new bone formation can be allegedly induced in or on a surface of an osseous tissue, or in or on a surface of a non-osseous tissue of a recipient by stimulating a bone formation stem cell.
Meanwhile, there is also a composition containing a fusion protein fused a PTH/PTHrP receptor agonist with a collagen-binding polypeptide fragment drived from a collagenase (Patent Literature 4). A parathyroid hormone (PTH) is used for an anabolic therapy of osteoporosis, an administration once a day is required. The composition can form a stable bind with collagen through a collagen-binding polypeptide fragment, and stay at an administration site for a long time period resisting body fluid circulation to enjoy longer half-life than PTH. Then, it can exert allegedly the same or higher effectiveness compared to PTH administration. In the example, it is administered intraperitoneally and increase of the bone density is observed.
Further, a fusion protein which a basic fibroblast growth factor (bFGF) instead of a PTH/PTHrP receptor agonist is bound to a collagen-binding polypeptide fragment, has been also known (Non Patent Literature 1).
Further, based on knowledge that it is useful to use a bone promoting factor in a treatment of a fracture, there is a bone formation promoting fusion protein prepared by binding a polypeptide having a collagen-binding domain derived from fibronectin with a bone formation promoting protein (Patent Literature 5). As examples of the bone formation promoting protein are named a growth factor belonging to a BMP (Bone Morphogenetic Proteins) subfamily, bFGF, and a thyroid hormone. In the example the polypeptide is prepared by using mRNA extracted from human kidney cells as a template thereof, bound with BMP2 or BMP7 as the bone formation promoting protein to prepare the bone formation promoting fusion protein. When the fusion protein was suspended with an osteoblast to be a mouse calvarium-derived established cell, administration of the bone formation promoting fusion protein caused allegedly concentration-dependent enhancement of alkali phosphatase activity on an osteoblast compared to administration of the above polypeptide.
Further, there is a composition for a treatment of a bone defect composed of a forming particle having at least 4 curved projections composed of calcium sulfate or the like and a material for a suspension (Patent Literature 6). A plurality of the projection of the forming particle can interlock each other to stabilize filling into a defect site, a binder capable of forming a gel of a collagen derivative or the like, or a bone morphogenic protein (BMP) can use as the suspension.
Further, there is a self-curing porous calcium phosphate composition which contains calcium phosphate, a blowing agent, and a biocompatible flocculant, and is mixed with a physiologically acceptable liquid, can releases a gas component by hydration of the blowing agent in the composition, gives at least 5% of porosity to the composition, and after curing the calcium phosphate composition exhibits a compressive strength of 1 MPa or more (Patent Literature 7). As the biocompatible flocculant collagen is disclosed and it is described that the composition may contain further a collagen exposure-treated substrate. The invention has a feature that a porous calcium phosphate composition is formed by a blowing agent, and in the example thereof a collagen exposure-treated substrate, sodium hydrogen carbonate and calcium phosphate as a blowing agent, and carboxymethyl cellulose as a flocculant were mixed to prepare a self-curing paste. By filling the self-curing paste in a defect formed at a rabbit distal femoral condyle, nearly complete healing was allegedly observed.
Additionally, there is a bone growth composition containing a particulate fibrous collagen component, and a calcium phosphate component, as well as a substance selected from the group consisting of a purified bone growth factor, a recombinant bone growth factor, a bone-marrow component, and demineralized bone and autologous bone (Patent Literature 8). The collagen component is cross-linked collagen or porous granular or other insoluble collagen. In the example, a calcium phosphate gel dispersion is kneaded with complex collagen, and after a cross-linking step by freeze-drying and thermal dewatering shaped into the particulate, pasted by adding blood, then transplanted to scattered bone. A defect site could be allegedly fixed firmly with the paste.